Neurological burden and outcomes of excessive ß-lactam serum concentrations of critically ill septic patients: a prospective cohort study.

BACKGROUND: Therapeutic drug monitoring (TDM) contributes to optimizing exposure to ß-lactam antibiotics. However, how excessive exposure to ß-lactams can increase the burden of care of critically ill patients is unclear. PATIENTS AND METHODS: In a prospective cohort study, we examined whether excessive ß-lactam serum concentrations contribute to neurological deterioration and the associated complications of adult septic patients without recent history of neurological disease treated with ß-lactams in a medical ICU. Excessive ß-lactam concentrations were defined as serum concentrations that exceeded the upper limit of the therapeutic range recommended by the French Societies of Pharmacology and Therapeutics (SFPT) and Anesthesia and Intensive Care Medicine (SFAR). Neurological deterioration was defined as an increase in the neurological Sequential Organ Failure Assessment score (nSOFA) of ≥1 between the day of starting treatment at admission and the day of TDM performed 2 days after treatment initiation. RESULTS: We included 119 patients [median age: 65 years; males: 78 (65.5%)] admitted for acute respiratory distress [59 (49.6%)] or septic shock [25 (21%)]. In adjusted logistic regression analysis, an excessive ß-lactam serum concentration was associated with neurological deterioration [OR (95% CI): 10.38 (3.23-33.35), P < 0.0001]. Furthermore, in adjusted linear regression analysis, an excessive ß-lactam serum concentration was associated with longer time to discharge alive (ß=0.346, P = 0.0007) and, among mechanically ventilated patients discharged alive, with longer time to extubation following the withdrawal of sedation (ß=0.248, P = 0.0030). CONCLUSIONS: These results suggest that excessive exposure to ß-lactams could complicate the management of septic patients in the ICU and confirm the clinical relevance of the upper concentration limits recommended for dose reduction.

Potential interactions between uraemic toxins and drugs: an application in kidney transplant recipients treated with calcineurin inhibitors.

BACKGROUND: The uraemic toxins that accumulate as renal function deteriorates can potentially affect drug pharmacokinetics. This study's objective was to determine whether plasma concentrations of certain uraemic toxins are correlated with blood concentrations of two immunosuppressants. METHODS: DRUGTOX was a cross-sectional study of 403 adult patients followed up after kidney transplantation and who had undergone therapeutic drug monitoring (TDM) of calcineurin inhibitors (tacrolimus or cyclosporin) between August 2019 and March 2020. For each patient, immunosuppressant trough concentrations (C0) were measured in whole blood samples and then normalized against the total daily dose (C0:D ratio). The sample was assayed for five uraemic toxins [urea, trimethylamine N-oxide (TMAO), indole acetic acid (IAA), p-cresylsulphate (PCS) and indoxylsulphate (IxS)] using liquid chromatography-tandem mass spectrometry. RESULTS: The median age was 56 years [interquartile range (IQR) 48-66] and the median estimated glomerular filtration rate was 41 mL/min/1.73 m2 (IQR 30-57). Age, sex, body mass index (BMI), urea, IxS and PCS were significantly associated with an increment in the tacrolimus C0:D ratio. A multivariate analysis revealed an independent association with IxS [odds ratio 1.36 (95% confidence interval 1.00-1.85)] after adjustment for sex, age and BMI, whereas adjustment for age weakened the association for PCS and urea. In a univariate logistic analysis, age, sex, BMI and the TMAO level (but not PCS, IxS, IAA or urea) were significantly associated with an increment in the cyclosporine C0:D ratio. CONCLUSIONS: Even though TDM and dose adaptation of immunosuppressants keep levels within the therapeutic window, increased exposure to tacrolimus (but not cyclosporine) is associated with an accumulation of PCS, IxS and urea.

Abnormal laboratory findings and plasma concentration monitoring of lopinavir and ritonavir in COVID-19.

It is not known whether the adverse events (AEs) associated with the administration of lopinavir and ritonavir (LPV/r) in the treatment of COVID-19 are concentration-dependent. In a retrospective study of 65 patients treated with LPV/r and therapeutic drug monitoring (TDM) for severe forms of COVID-19 (median age: 67; males: 41 [63.1%]), 33 (50.8%) displayed a grade ≥2 increase in plasma levels of hepatobiliary markers, lipase and/or triglycerides. A causal relationship between LPV/r and the AE was suspected in 9 of the 65 patients (13.8%). At 400 mg b.i.d., the plasma trough concentrations of LPV/r were high and showed marked interindividual variability (median [interquartile range]: 16,600 [11,430-20,842] ng/ml for lopinavir and 501 [247-891] ng/ml for ritonavir). The trough lopinavir concentration was negatively correlated with body mass index, while the trough ritonavir concentration was positively correlated with age and negatively correlated with prothrombin activity. However, the occurrence of abnormal laboratory values was not associated with higher trough plasma concentrations of LPV/r. Further studies will be needed to determine the value of TDM in LPV/r-treated patients with COVID-19.

A Study of Associations Between Plasma Metformin Concentration, Lactic Acidosis, and Mortality in an Emergency Hospitalization Context.

OBJECTIVES: To determine the plasma metformin concentration threshold associated with lactic acidosis and analyze the outcome in metformin-treated patients with lactic acidosis hospitalized in an emergency context. DESIGN: A retrospective, observational, single-center study. SETTING: Emergency department and ICUs at Amiens University Hospital (Amiens, France). PATIENTS: All consecutive patients with data on arterial lactate and pH up to 12 hours before or after a plasma metformin assay within 24 hours of admission, over a 9.7-year period. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The study population consisted of 194 metformin-treated diabetic patients (median age: 68.6; males: 113 [58.2%]); 163 (84%) had acute kidney injury, which was associated variously with dehydration (45.4%), sepsis (41.1%), cardiogenic shock (20.9%), and diabetic ketoacidosis (16%). Eighty-seven patients (44.8%) had lactic acidosis defined as an arterial blood pH less than 7.35 and a lactate concentration greater than or equal to 4 mM, and 38 of them (43.7%) died in the ICU. A receiver operating characteristic curve analysis showed that a metformin concentration threshold of 9.9 mg/L was significantly associated with the occurrence of lactic acidosis (specificity: 92.9%; sensitivity: 67.1%; area under the receiver operating characteristic curve: 0.83; p < 0.0001). Among lactic acidosis-positive patients, however, in-ICU death was less frequent when the metformin concentration was greater than or equal to 9.9 mg/L (33.9% vs 61.3% for < 9.9 mg/L; p = 0.0252). After adjustment for the Simplified Acute Physiology Score II, in-ICU death was positively associated with prothrombin activity less than 70% and negatively associated with the initiation of renal replacement therapy at admission. CONCLUSIONS: In metformin-treated patients admitted in an emergency context, a plasma metformin concentration greater than or equal to 9.9 mg/L was strongly associated with the presence of lactic acidosis. This threshold may assist with the delicate decision of whether or not to initiate renal replacement therapy. Indeed, the outcome of lactic acidosis might depend on the prompt initiation of renal replacement therapy-especially when liver failure reduces lactate elimination.

Pitfalls of toxicological investigations in hair, bones, and nails in extensively decomposed bodies: illustration with two cases.

It is difficult to carry out toxicological investigations in biological samples collected from extensively decomposed bodies and to interpret obtained results as several pitfalls should be considered: redistribution phenomena, degradation of xenobiotics during the postmortem period, contamination by putrefaction fluids, and external contamination. This work aims to present two cases in order to illustrate and discuss these difficulties in this tricky situation. Case#1: the body of a 30-year-old woman was found in a wooded area (1 month after she has been reported missing by her family): hair and a femur section were sampled. Case#2: the decomposed corpse of a 52-year-old man was found in a ditch: hair and nails were sampled. After decontamination steps, toxicological investigations were performed using liquid chromatography with high-resolution mass spectrometry and tandem mass spectrometry detection methods. In case#1, the same drugs or metabolites (benzodiazepines, propranolol, tramadol, acetaminophen, paroxetine, and oxetorone) were detected in hair and in bone specimens. This result combination strongly suggests intakes close to the time of death for three of them (oxazepam, lormetazepam, and propranolol). In case#2, results of toxicological investigations in hair and nails [(hair/nail concentration in ng/mg) nordiazepam (1.12/1.06), oxazepam (0.113/0.042), zolpidem (0.211/< 0.01), hydroxyzine (0.362/< 0.01), and cetirizine (0.872/1.110)] were both consistent with several drug intakes but were not contributory to cause of death determination. In case of positive toxicological results in biological samples collected from extensively decomposed bodies (such as hair, bones, or nails), it is challenging to determine the time, and even more, the level of the dose of exposure(s).

Validation and Application of an HPLC-DAD Method for Routine Therapeutic Drug Monitoring of Ceftobiprole.

Ceftobiprole is a fifth-generation cephalosporin approved for the treatment of pneumonia, with a broad antibacterial spectrum, including potent activity against methicillin-resistant Staphylococcus aureus As for the other cephalosporins, high pharmacokinetic variability and concentration-dependent neurotoxicity are expected. We describe here the first simple and rapid analytical method intended for ceftobiprole serum concentration monitoring. We report the data of 5 patients treated with ceftobiprole, among who 2 developed reversible neurological disorders with high ceftobiprole serum concentration.

Effects of Smoking Exposure in Infants on Gastroesophageal Reflux as a Function of the Sleep-Wakefulness State.

OBJECTIVE: To determine whether perinatal smoking exposure is associated with gastroesophageal reflux (GER)-related changes in sleep-wakefulness states in neonates. STUDY DESIGN: Thirty-one neonates, referred for the investigation of suspected GER, were recruited and underwent multichannel impedance-pH monitoring and synchronized 8- to 12-hour polysomnography. The infants' exposure to tobacco smoke was estimated by means of a urine cotinine assay. The total number, frequency (h-1), and mean duration (minutes) of GER-pH (reflux events detected by the pH electrode only) and GER-imp (reflux events with bolus movement detected by impedance) events were determined. Intergroup differences (smoking-exposed group vs nonexposed group) were probed with nonparametric, unpaired Mann-Whitney U tests. A χ2 test was used to assess a possible intergroup difference in bolus retrograde migration during GER-imp events. RESULTS: According to the urine cotinine assay, 21 of the 31 neonates had been exposed to cigarette smoke during the perinatal period. The number (and frequency) of GER-imp was significantly greater (P = .016) in the exposed group (29 [0-90]) than in the nonexposed group (12 [2-35]). Migration of the esophageal bolus from the distal segment to the most proximal segment was significantly more frequent (P = .016) in the exposed group (83% of GER) than in the nonexposed group (41%). The GER pattern associated with smoking exposure was particularly obvious during Rapid eye movement sleep. CONCLUSIONS: The more frequent occurrence and greater proximal migration of GER-imp in the smoking-exposed group (especially during rapid eye movement sleep) may have clinical relevance. Smoking exposure is a preventable risk factor for limiting the occurrence of GER in neonates.

Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients.

This retrospective cohort study included 53 patients admitted to the intensive care unit (ICU), with an average age of 69 years, without neurologic disorder before initiation of a continuous piperacillin infusion at the standard dose and who underwent piperacillin serum concentration monitoring. Among them, 23 developed a neurologic disorder for which the piperacillin causality was chronologically and semiologically suggestive. A concentration threshold of 157.2 mg/liter independently predicted neurotoxicity with 96.7% specificity and 52.2% sensitivity and may constitute a limitation when targeting less susceptible pathogens.

Efficacy and safety of nicotinamide in haemodialysis patients: the NICOREN study.

BACKGROUND: Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease. METHODS: The NICOREN multicentre, open-label and randomized study was designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N -methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety. RESULTS: After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 ± 0.4 to 1.8 ± 0.5 and 2.3 ± 0.5 to 1.7 ± 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001). CONCLUSIONS: Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects.

N-methyl-2-pyridone-5-carboxamide (2PY)-Major Metabolite of Nicotinamide: An Update on an Old Uremic Toxin.

N-methyl-2-pyridone-5-carboxamide (2PY, a major metabolite of nicotinamide, NAM) was recently identified as a uremic toxin. Recent interventional trials using NAM to treat high levels of phosphorus in end-stage renal disease have highlighted new potential uremic toxicities of 2PY. In the context of uremia, the accumulation of 2PY could be harmful-perhaps by inhibiting poly (ADP-ribose) polymerase-1 activity. Here, we review recently published data on 2PY's metabolism and toxicological profile.

[Drug use and driving]. / Médicaments et conduite automobile.

Some drugs are known to impair driving because they can change the vision or hearing, and/or disrupt the intellectual or motor abilities: impaired vigilance, sedation, disinhibition effect, the coordination of movement disorders and the balance. The doctor during prescribing and the pharmacist during deliverance of drug treatment should inform their patients of the potential risks of drugs on driving or operating machinery. The driver has direct responsibility, who hired him and him alone, to follow the medical advice received. The pictograms on the outer packaging of medicinal products intended to classify substances according to their risk driving: The driver can whether to observe simple precautions (level one "be prudent"), or follow the advice of a health professional (level two "be very careful"), or if it is totally not drive (level three "danger caution: do not drive"). This classification only evaluates the intrinsic danger of drugs but not the individual variability. Medicines should be taken into account also the conditions for which the medication is prescribed. It is important to inform the patient on several points.

The end-of-treatment ribavirin concentration predicts hepatitis C virus relapse.

BACKGROUND: The optimization of combination therapy with ribavirin (RBV) and pegylated interferon alpha has substantially improved sustained virologic response (SVR) rates and lowered virologic relapse rates in patients infected with hepatitis C virus (HCV). In this study, we performed an analysis of the relationship between the end-of-treatment plasma RBV concentration and virologic relapse. METHODS: Thirty-four patients with HCV treated with pegylated interferon/RBV and with an end-of-treatment response were assayed for plasma RBV concentration using liquid chromatography assay coupled to tandem mass-spectrometric detection on the last day of the treatment. Clinical data and the concentration of RBV were compared between patients classified as either relapsers or nonrelapsers. RESULTS: Eleven patients (32.4%) relapsed and 23 patients (67.6%) achieved an SVR. The mean plasma RBV concentration on the last day of treatment was 1380 ± 312 ng/mL for relapsers and 2278 ± 569 ng/mL for SVR patients (P < 0.0001). A receiver operating characteristic analysis showed that a threshold of 1960 ng/mL was associated with the greatest sensitivity and specificity (100% and 83%, respectively, with an area under the curve of 0.94; P < 0.0001) for discriminating between patients who relapsed and those who did not. A univariate logistic regression analysis indicated that a plasma RBV concentration of <1960 ng/mL at the end of the treatment was strongly associated with relapse (odds ratio, 55; 95% confidence interval, 7.24-∞; P = 0.0001) independently of age, body weight, RBV dose, baseline viral load, the interleukin-28B genotype, and response to previous courses of treatment. CONCLUSIONS: Our study results highlight the relevance of measuring plasma RBV concentrations during and at the end of HCV treatment, with a view to avoiding virologic relapse.

Establishment of a database of metformin plasma concentrations and erythrocyte levels in normal and emergency situations.

BACKGROUND AND OBJECTIVES: Knowledge of blood metformin concentrations may be crucial for adapting the dose to the patient's kidney function and investigating a putative link between this drug and lactic acidosis. We therefore established the first database of blood metformin concentrations. METHODS: In order to provide cross-sectional data from clinical practice in a university medical centre, the authors retrospectively reviewed all available metformin plasma concentrations and erythrocyte level results (all of which were measured using the same assay technique). The assays had been requested for either dose adjustment in relation to the patient's renal status or screening for potential metformin accumulation, metformin overdose or lactic acidosis. RESULTS: A total of 798 metformin assays were performed in 467 patients. The mean ± SD (range) plasma concentrations and erythrocyte levels were 2.7 ± 7.3 (0-113) mg/L and 2.0 ± 4.4 (0-61) mg/L, respectively (published therapeutic values: 0.5 ± 0.4 mg/L and 0.8 ± 0.4 mg/L, respectively). Four plasma concentration categories were defined on a pragmatic basis: undetectable (9.7%), therapeutic range (40.6%), slight-to-moderate elevation (42.6%) and marked elevation (7.1%). CONCLUSION: Greater knowledge of blood metformin concentrations is required to adjust treatment and avoid wrongly incriminating the drug in lactic acidosis. Establishment of the first database of blood metformin concentrations may help physicians to better evaluate metformin use and dosage levels (particularly in elderly patients and those with poor kidney function), determine the presence and intensity of metformin accumulation and, ultimately, establish the prognosis of the latter condition.

Development and formulation of a 0.2% oral solution of midazolam containing gamma-cyclodextrin.

In absence of dedicated children formulation, intravenous formulations of midazolam, which exhibit strong bitterness, are occasionally used for oral or sublingual administration. In order to improve the quality and the acceptance by children of a midazolam anesthesia premedication, a new 0.2% (w/v) aqueous solution for oral administration has been prepared. The final formulation was obtained by the adjunction of a sweetener (sucralose), an aroma (orange aroma) and gamma-cyclodextrin to a citric acid solution of midazolam. The gamma-cyclodextrin forms an inclusion complex with the hydrophobic midazolam as evidenced using nuclear magnetic resonance spectroscopy (stoichiometry 1:1, K=283 M(-1)). A sterile filtration method was selected for the formulation microbial preservation using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). Finally, a routine high performance liquid chromatography (HPLC) method is proposed for the quantitative determination of global midazolam amount in the pharmaceutical preparation.